This invention relates to certain N-acyl and carboxyl derivatives of the new antibiotic thienamycin. Such derivatives are useful as antibiotics. This invention also relates to processes for the preparation of such compounds, pharmaceutical compositions comprising such compounds, and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
Thienamycin (I), is disclosed and claimed in co-pending, commonly assigned U.S. patent application Ser. No. 526,992, filed Nov. 25, 1974 (now U.S. Pat. No. 3,950,357, issued Apr. 13, 1976), which patent is incorporated herein by reference since thienamycin may serve as a starting material for the compounds of the present invention. ##STR2##
Thienamycin and all of its isomers (in pure form and as mixtures) are also obtainable by the total synthesis disclosed and claimed in co-pending, commonly assigned U.S. patent application Ser. No. 833,210 (Sept. 15, 1977). This application is incorporated herein by reference to the extent that it makes available all isomers of I as starting materials in the preparation of the compounds of the present invention.
The N-acylated, carboxyl derivatives of thienamycin of the present invention may be depicted by the following generic structural formula (II): ##STR3## or, more conveniently, by the symbol: ##STR4## wherein "Th" symbolizes the bicyclic nucleus of Thienamycin and the OH, amino and carboxyl groups of thienamycin are illustrated.
R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen (R.sup.1 and R.sup.2 are not both hydrogen) or an acyl group. The most preferred compounds of this invention are those wherein R.sup.1 is hydrogen and R.sup.2 is acyl. The term "acyl" is by definition inclusive of the alkanoyls including derivatives and analogues thereof such as thio analogues wherein the carbonyl oxygen is replaced by sulphur, diacyl radicals wherein R.sup.1 and R.sup.2 are joined together; as well as the sulphur and phosphorous acyl analogues such as substituted sulfonyl-, sulfinyl- and sulfenyl-radicals, and substituted P (III and V) radicals such as the substituted phosphorous-, phosphoric-, phosphonous- and phosphonic-radicals, respectively. Such acyl radicals of the present invention are further defined below.
X is oxygen, sulphur or NR' (R'.dbd.H or R); and R is, inter alia, representatively selected from the group consisting of conventional blocking groups such as trialkylsilyl, substituted and unsubstituted benzyl, acyl and the pharmaceutically acceptable salt, ester and amide moieties known in the bicylic .beta.-lactam antibiotic art; the definition of R is given in greater detail below.
There is a continuing need for new antibiotics for unfortuantely there is no static effectiveness of a given antibiotic because continued wide scale usage of any such antibiotic selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
Unexpectedly, it has been found that the compounds of the present invention are broad spectrum antibiotics, which are useful in animal and human therapy and in inanimate systems.
Thus, it is an object of the present invention to provide a novel class of antibiotics which possess the basic nuclear structure of the antibiotic thienamycin but which are characterized as N-acylated, carboxyl derivatives thereof. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. Aureus, B. subtilis, and Strept. pyogenes and gram negative bacteria such as E. coli, and Salmonella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.